tbuckley/cabot-search huggingface dataset:
A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes
Authors: Joshua J. Gruber, Anosheh Afghahi, Kirsten Timms, Alyssa DeWees, Wyatt Gross, Vasily N. Aushev, Hsin-Ta Wu, Mustafa Balcioglu, Himanshu Sethi, Danika Scott, Jessica Foran, Alex McMillan, James M. Ford, Melinda L. Telli
Journal: Nature Cancer (2022)

Abstract Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (g BRCA1 / 2 )-mutant advanced breast cancer, but its activity beyond g BRCA1 / 2 is poorly understood. We conducted Talazoparib Beyond BRCA ( NCT02401347 ), an open-label phase II trial, to evaluate talazoparib in patients with pretreated advanced HER2-negative breast cancer ( n = 13) or other solid tumors ( n = 7) with mutations in homologous recombination (HR) pathway genes other than BRCA1 and BRCA2 . In patients with breast cancer, four patients had a Response Evaluation Criteria in Solid Tumors (RECIST) partial response (overall response rate, 31%), and three additional patients had stable disease of ≥6 months (clinical benefit rate, 54%). All patients with germline mutations in PALB2 ( g PALB2 ; encoding partner and localizer of BRCA2) had treatment-associated tumor regression. Tumor or plasma circulating tumor DNA (ctDNA) HR deficiency (HRD) scores were correlated with treatment outcomes and were increased in all g PALB2 tumors. In addition, a g PALB2 -associated mutational signature was associated with tumor response. Thus, talazoparib has been demonstrated to have efficacy in patients with advanced breast cancer who have g PALB2 mutations, showing activity in the context of HR pathway gene mutations beyond g BRCA1 / 2 .
Life expectancy changes since COVID-19
Authors: Jonas Schöley, José Manuel Aburto, Ilya Kashnitsky, Maxi S. Kniffka, Luyin Zhang, Hannaliis Jaadla, Jennifer B. Dowd, Ridhi Kashyap
Journal: Nature Human Behaviour (2022)

The COVID-19 pandemic triggered an unprecedented rise in mortality that translated into life expectancy losses around the world, with only a few exceptions. We estimate life expectancy changes in 29 countries since 2020 (including most of Europe, the United States and Chile), attribute them to mortality changes by age group and compare them with historic life expectancy shocks. Our results show divergence in mortality impacts of the pandemic in 2021. While countries in western Europe experienced bounce backs from life expectancy losses of 2020, eastern Europe and the United States witnessed sustained and substantial life expectancy deficits. Life expectancy deficits during fall/winter 2021 among people ages 60+ and <60 were negatively correlated with measures of vaccination uptake across countries (r
Health‐related quality of life in reduced‐intensity hematopoietic cell transplantation based on donor availability in patients aged 50–75 with advanced myelodysplastic syndrome: <scp>BMT CTN</scp> 1102
Authors: Rachel Cusatis, Michael J. Martens, Ryotaro Nakamura, Corey S. Cutler, Wael Saber, Stephanie J. Lee, Brent R. Logan, Bronwen E. Shaw, Alyssa Gregory, Anita D'Souza, Betty K. Hamilton, Mary M. Horowitz, Kathryn E. Flynn
Journal: American Journal of Hematology (2022)

Abstract For myelodysplastic syndrome (MDS), allogeneic hematopoietic cell transplantation (alloHCT) is the only available curative therapy. The Blood and Marrow Transplant Clinical Trials Network study 1102 (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial based on matched donor availability in adults aged 50–75 with higher risk de novo MDS who were candidates for reduced‐intensity conditioning (RIC) alloHCT. The primary analysis showed that those who received alloHCT had a survival benefit, but whether this is at the cost of worse quality of life (QOL) has not been described in detail. English‐ and Spanish‐speaking trial participants completed the Functional Assessment of Cancer Therapy—General (FACT‐G), the SF‐36, and the EQ‐5D, at enrollment, every 6 months until 24 months, and 36 months. We compared patient‐reported outcome (PRO) scores between study arms using an inverse probability weighted‐independent estimating equation (IPW‐IEE) model. Between January 2014 and November 2018, 384 subjects (median age 66.7 years, range: 50.1–75.3) enrolled at 34 centers. PRO completion rates were generally high at 65%–78%. The PRO trajectories for both arms were similar, with most decreasing or stable from baseline to 6 months and improving thereafter. Baseline PRO scores were the most consistent independent predictors of subsequent QOL outcomes and survival, even after controlling for clinical and patient‐level factors. For older adults with MDS, the survival advantage associated with donor availability and alloHCT did not come at the cost of worse QOL. These results should reassure older patients and clinicians who prefer a curative approach to treating MDS.
Early-Onset Type 2 Diabetes and Mood, Anxiety, and Stress-Related Disorders: A Genetically Informative Register-Based Cohort Study
Authors: Shengxin Liu, Marica Leone, Jonas F. Ludvigsson, Paul Lichtenstein, Soffia Gudbjörnsdottir, Mikael Landén, Sarah E. Bergen, Mark J. Taylor, Henrik Larsson, Ralf Kuja-Halkola, Agnieszka Butwicka
Journal: Diabetes Care (2022)

OBJECTIVE To assess the association and familial coaggregation between early-onset type 2 diabetes (diagnosed before age 45 years) and mood, anxiety, and stress-related disorders and estimate the contribution of genetic and environmental factors to their co-occurrence. RESEARCH DESIGN AND METHODS This population-based cohort study included individuals born in Sweden during 1968–1998, from whom pairs of full siblings, half-siblings, and cousins were identified. Information on diagnoses of early-onset type 2 diabetes and mood (including unipolar depression and bipolar disorder), anxiety, and stress-related disorders was obtained from the National Patient Register. Logistic and Cox regression models were used to assess the phenotypic association and familial coaggregation between type 2 diabetes and psychiatric disorders. Quantitative genetic modeling was conducted in full and maternal half-sibling pairs to estimate the relative contributions of genetic and environmental factors to the association. RESULTS Among a total of 3,061,192 individuals, 7,896 (0.3%) were diagnosed with early-onset type 2 diabetes. These individuals had higher risks of any diagnosis (odds ratio [OR] 3.62 [95% CI 3.44, 3.80]) and specific diagnosis of unipolar depression (3.97 [3.75, 4.22]), bipolar disorder (4.17 [3.68, 4.73]), anxiety (3.76 [3.54, 3.99]), and stress-related disorders (3.35 [3.11, 3.61]). Relatives of individuals with early-onset type 2 diabetes also had higher overall risks of the examined psychiatric disorders (ORs 1.03–1.57). These associations are largely explained by genetic factors (51–78%), with the rest explained by nonshared environmental factors. CONCLUSIONS Our findings highlight the burden of mood, anxiety, and stress-related disorders in early-onset type 2 diabetes and demonstrate that shared familial liability may contribute to their co-occurrence, suggesting that in the future research investigators should aim to identify shared risk factors and ultimately refine preventive and intervention strategies.
The 5-Hydroxymethylcytosine Landscape of Prostate Cancer
Authors: Martin Sjöström, Shuang G. Zhao, Samuel Levy, Meng Zhang, Yuhong Ning, Raunak Shrestha, Arian Lundberg, Cameron Herberts, Adam Foye, Rahul Aggarwal, Junjie T. Hua, Haolong Li, Anna Bergamaschi, Corinne Maurice-Dror, Ashutosh Maheshwari, Sujun Chen, Sarah W.S. Ng, Wenbin Ye, Jessica Petricca, Michael Fraser, Lisa Chesner, Marc D. Perry, Thaidy Moreno-Rodriguez, William S. Chen, Joshi J. Alumkal, Jonathan Chou, Alicia K. Morgans, Tomasz M. Beer, George V. Thomas, Martin Gleave, Paul Lloyd, Tierney Phillips, Erin McCarthy, Michael C. Haffner, Amina Zoubeidi, Matti Annala, Robert E. Reiter, Matthew B. Rettig, Owen N. Witte, Lawrence Fong, Rohit Bose, Franklin W. Huang, Jianhua Luo, Anders Bjartell, Joshua M. Lang, Nupam P. Mahajan, Primo N. Lara, Christopher P. Evans, Phuoc T. Tran, Edwin M. Posadas, Chuan He, Xiao-Long Cui, Jiaoti Huang, Wilbert Zwart, Luke A. Gilbert, Christopher A. Maher, Paul C. Boutros, Kim N. Chi, Alan Ashworth, Eric J. Small, Housheng H. He, Alexander W. Wyatt, David A. Quigley, Felix Y. Feng
Journal: Cancer Research (2022)

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.
Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex
Authors: Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L. Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N. Westin, Sanghoon Lee, Anil K. Sood, Liuqing Yang, Gabriel N. Hortobagyi, Dihua Yu, Mien-Chie Hung
Journal: Nature Cancer (2022)

Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor growth and improve survival of mice in PARP inhibitor-/platinum-resistant tumor xenograft models. Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK–p-Tyr19-CDK9 expression.
Cataract surgeon who missed NHS operations while doing private work is struck off
Authors: Clare Dyer
Journal: BMJ (2022)

<h3>ABSTRACT</h3> The healthy human skin microbiome is shaped by skin site physiology, individual-specific factors, and is largely stable over time despite significant environmental perturbation. Studies identifying these characteristics used shotgun metagenomic sequencing for high resolution reconstruction of the bacteria, fungi, and viruses in the community. However, these conclusions were drawn from a relatively small proportion of the total sequence reads analyzable by mapping to known reference genomes. ‘Reference-free’ approaches, based on <i>de novo</i> assembly of reads into genome fragments, are also limited in their ability to capture low abundance species, small genomes, and to discriminate between more similar genomes. To account for the large fraction of non-human unmapped reads on the skin—referred to as microbial ‘dark matter’—we used a hybrid <i>de novo</i> and reference-based approach to annotate a metagenomic dataset of 698 healthy human skin samples. This approach reduced the overall proportion of uncharacterized reads from 42% to 17%. With our refined characterization, we revisited assumptions about the skin microbiome, and demonstrated higher biodiversity and lower stability, particularly in dry and moist skin sites. To investigate hypotheses underlying stability, we examined growth dynamics and interspecies interactions in these communities. Surprisingly, even though most skin sites were relatively stable, many dominant skin microbes, including <i>Cutibacterium acnes</i> and staphylococci, were actively growing in the skin, with poor or no relationship between growth rate and relative abundance, suggesting that host selection or interspecies competition may be important factors maintaining community homeostasis. To investigate other mechanisms facilitating adaptation to a specific skin site, we identified <i>Staphylococcus epidermidis</i> genes that are likely involved in stress response and provide mechanisms essential for growth in oily sites. Finally, horizontal gene transfer—another mechanism of competition by which strains may swap antagonistic or virulent coding regions—was relatively limited in healthy skin, but suggested exchange of different metabolic and environmental tolerance pathways. Altogether, our findings underscore the value of a combined reference-based and <i>de novo</i> approach to provide significant new insights into microbial composition, physiology, and interspecies interactions to maintain community homeostasis in the healthy human skin microbiome.
Targeted profiling of human extrachromosomal DNA by CRISPR-CATCH
Authors: King L. Hung, Jens Luebeck, Siavash R. Dehkordi, Caterina I. Colón, Rui Li, Ivy Tsz-Lo Wong, Ceyda Coruh, Prashanthi Dharanipragada, Shirley H. Lomeli, Natasha E. Weiser, Gatien Moriceau, Xiao Zhang, Chris Bailey, Kathleen E. Houlahan, Wenting Yang, Rocío Chamorro González, Charles Swanton, Christina Curtis, Mariam Jamal-Hanjani, Anton G. Henssen, Julie A. Law, William J. Greenleaf, Roger S. Lo, Paul S. Mischel, Vineet Bafna, Howard Y. Chang
Journal: Nature Genetics (2022)

Abstract Extrachromosomal DNA (ecDNA) is a common mode of oncogene amplification but is challenging to analyze. Here, we adapt CRISPR-CATCH, in vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis of agarose-entrapped genomic DNA, previously developed for bacterial chromosome segments, to isolate megabase-sized human ecDNAs. We demonstrate strong enrichment of ecDNA molecules containing EGFR , FGFR2 and MYC from human cancer cells and NRAS ecDNA from human metastatic melanoma with acquired therapeutic resistance. Targeted enrichment of ecDNA versus chromosomal DNA enabled phasing of genetic variants, identified the presence of an EGFRvIII mutation exclusively on ecDNAs and supported an excision model of ecDNA genesis in a glioblastoma model. CRISPR-CATCH followed by nanopore sequencing enabled single-molecule ecDNA methylation profiling and revealed hypomethylation of the EGFR promoter on ecDNAs. We distinguished heterogeneous ecDNA species within the same sample by size and sequence with base-pair resolution and discovered functionally specialized ecDNAs that amplify select enhancers or oncogene-coding sequences.
Gut Parabacteroides merdae protects against cardiovascular damage by enhancing branched-chain amino acid catabolism
Authors: Shanshan Qiao, Chang Liu, Li Sun, Tao Wang, Huanqin Dai, Kai Wang, Li Bao, Hantian Li, Wenzhao Wang, Shuang-Jiang Liu, Hongwei Liu
Journal: Nature Metabolism (2022)
Bioabsorbable, elastomer-coated magnesium alloy coils for treating saccular cerebrovascular aneurysms
Authors: Seungil Kim, Kamil W. Nowicki, Sangho Ye, Kyeongwoo Jang, Moataz Elsisy, Mohamed Ibrahim, Youngjae Chun, Bradley A. Gross, Robert M. Friedlander, William R. Wagner
Journal: Biomaterials (2022)
Patterns of Population Structure and Introgression Among Recently Differentiated <i>Drosophila melanogaster</i> Populations
Authors: Jenn M Coughlan, Andrius J Dagilis, Antonio Serrato-Capuchina, Hope Elias, David Peede, Kristin Isbell, Dean M Castillo, Brandon S Cooper, Daniel R Matute
Journal: Molecular Biology and Evolution (2022)

Abstract Despite a century of genetic analysis, the evolutionary processes that have generated the patterns of exceptional genetic and phenotypic variation in the model organism Drosophila melanogaster remains poorly understood. In particular, how genetic variation is partitioned within its putative ancestral range in Southern Africa remains unresolved. Here, we study patterns of population genetic structure, admixture, and the spatial structuring of candidate incompatibility alleles across a global sample, including 223 new accessions, predominantly from remote regions in Southern Africa. We identify nine major ancestries, six that primarily occur in Africa and one that has not been previously described. We find evidence for both contemporary and historical admixture between ancestries, with admixture rates varying both within and between continents. For example, while previous work has highlighted an admixture zone between broadly defined African and European ancestries in the Caribbean and southeastern USA, we identify West African ancestry as the most likely African contributor. Moreover, loci showing the strongest signal of introgression between West Africa and the Caribbean/southeastern USA include several genes relating to neurological development and male courtship behavior, in line with previous work showing shared mating behaviors between these regions. Finally, while we hypothesized that potential incompatibility loci may contribute to population genetic structure across the range of D. melanogaster; these loci are, on average, not highly differentiated between ancestries. This work contributes to our understanding of the evolutionary history of a key model system, and provides insight into the partitioning of diversity across its range.
Effects of State Opioid Prescribing Laws on Use of Opioid and Other Pain Treatments Among Commercially Insured U.S. Adults
Authors: Jeffrey Katz
Journal: Annals of Internal Medicine (2022)

LettersOctober 2022Effects of State Opioid Prescribing Laws on Use of Opioid and Other Pain Treatments Among Commercially Insured U.S. AdultsJeffrey Katz, MDJeffrey Katz, MDVA Southern Nevada Healthcare System, North Las Vegas, NevadaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L22-0247 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: McGinty and colleagues' article (1) provides valuable insight into the opioid crisis created by the medical establishment in the 1990s. However, they do not mention the history of the United States' first opioid epidemic and its resolution, as described by David T. Courtwright in his book Dark Paradise. This work reviews the opioid epidemic after the Civil War, when it affected 1 in 200 persons in the United States.Many incorrectly believe that the passage of the Harrison Narcotic Act in 1914 resolved that first crisis; the act imposed fees, restrictions, and tracking procedures for the production ...References1. McGinty EE, Bicket MC, Seewald NJ, et al. Effects of state opioid prescribing laws on use of opioid and other pain treatments among commercially insured U.S. adults. Ann Intern Med. 2022;175:617-27. [PMID: 35286141] LinkGoogle Scholar2. Courtwright DT. Preventing and treating narcotic addiction—century of federal drug control. N Engl J Med. 2015;373:2095-7. [PMID: 26605925] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAuthors: Jeffrey Katz, MDAffiliations: VA Southern Nevada Healthcare System, North Las Vegas, NevadaDisclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L22-0247. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEffects of State Opioid Prescribing Laws on Use of Opioid and Other Pain Treatments Among Commercially Insured U.S. Adults Emma E. McGinty , Mark C. Bicket , Nicholas J. Seewald , Elizabeth A. Stuart , G. Caleb Alexander , Colleen L. Barry , Alexander D. McCourt , and Lainie Rutkow Metrics October 2022Volume 175, Issue 10Page: W118KeywordsDrug regulationHeadachesLower back painNeuropathic painOpioidsPainPain managementPrevention, policy, and public healthPublic policyTreatment guidelines ePublished: 18 October 2022 Issue Published: October 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Apixaban Versus Rivaroxaban in Patients With Atrial Fibrillation and Valvular Heart Disease
Authors: Ghadeer K. Dawwas, Adam Cuker, Geoffrey D. Barnes, James D. Lewis, Sean Hennessy
Journal: Annals of Internal Medicine (2022)

Although apixaban and rivaroxaban are commonly used in patients with atrial fibrillation (AF) and valvular heart disease (VHD), there is limited evidence comparing the 2 drugs in these patients.